DE2714891A1 - A NEW PROCESS FOR THE PRODUCTION OF 6 BETA, 7-METHYLENE-3-OXO-4-EN-STEROIDS - Google Patents

Description

A new process for the preparation of 6ß, 7-methylene-3-oxo-4-ene steroids.

The invention relates to a novel process for the preparation of 6ß, T-methylene-S-oxc ^ -en especially those of the general formula

(CH ₂ ) _n

where η denotes the number 1 or 2 and R denotes an optionally ketalized oxo group, an optionally etherified one or esterified hydroxyl group together with a hydrogen atom or an optionally substituted lower aliphatic hydrocarbon radical, or one hydrogen atom together with one optionally

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represents substituted lower alkyl.

The term "lower", wherever it occurs in connection with an organic residue, denotes a corresponding radical with at most 7, preferably with at most 4 carbon atoms. The symbol η preferably means the number 1.

A lower alkyl radical is e.g. n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, a branched or preferably straight pentyl, hexyl or heptyl radical, but above all an ethyl or methyl radical. As a lower aliphatic hydrocarbon radical, a lower alkyl radical, e.g. to consider one of the already mentioned, which optionally has one or two multiple bonds, i.e. Double bonds or acetylene bonds, such as e.g. a lower alkenyl, lower alkynyl and allenyl radical, for example a vinyl, allyl, methallyl, propargyl, Hexadiynyl and especially ethynyl radical.

The already characterized lower aliphatic hydrocarbon radical or lower alkyl radical can be substituted by one or more, identical or different substituents, which are in front of especially in the α- and / or ß-position (according to the

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20 or 21 position of the steroid numbering). Suitable substituents are optionally etherified and esterified hydroxyl groups, optionally acetalized or ketalized oxo groups, such as i _n an acetyl or Hydroxyacetylrest, and optionally esterified carboxyl groups into consideration, where the carboxyl groups may also be in the form of their salts, in particular alkali metal salts. Esterified carboxyl group is not only to be understood as a carboxyl group which is present in the form of its ester, in particular one with lower alkanols, but also that which closes a 6- or, in particular, 5-membered lactone ring with a suitably removed hydroxyl group occurring as a substituent. In particular, such a lactone ring is formed including the 17β-hydroxyl group, and analogous cyclic acetals and ethers (in which an acetalized formyl group or an etherified hydroxymethyl group occurs instead of the esterified carboxyl group) are also included in the meaning of the optionally substituted hydrocarbon radicals discussed.

Accordingly, a form of the radical R mentioned is to be particularly emphasized by the sub-formula

CH ₂ -CH ₂

———— 0

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represented, wherein R has two hydrogen atoms, an oxo group, or represents a lower alkoxy group together with a hydrogen atom.

The lower aliphatic carbon

hydrogen residue can also be disubstituted by a disubstituted one Amino group, e.g., a di-lower alkylamino group such as the dimethylamine or diethylamino group. A particularly noteworthy meaning of the symbol R is that in which R is a / 3-oriented hydroxyl group together with a 7-di-lower alkylaminopropyl, in particular 7-dimethylaminopropyl or 7-diethylaminopropyl residue represents.

A ketalized oxo group is derived

in particular of lower alkanols, e.g. of methanol or ethanol, or preferably of α- or ß-lower alkanediols, e.g. 1,2- or 1,3-propanediol or especially ethylene glycol; however, it can also be used by the corresponding sulfur analogues of the alcohols mentioned and instead of one or both oxygen atoms Have sulfur atoms.

An etherified hydroxyl group can be a lower alkoxy, in particular a straight-chain lower alkoxy group, e.g. the methoxy, ethoxy, propoxy and butoxy group; but above all it is easy one through one

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removable protective group etherified hydroxyl group. as the ethereal protective group are the following in particular: a by aryl, especially phenyl, lower alkyl radical substituted in the 1-position, e.g. a benzyl and triphenylmethyl radical; one by lower alkoxy groups, like the above-mentioned lower alkyl radical substituted in the 1-position, e.g. the 1-butoxyethyl or 1-methoxyethyl radical; also heterocyclic radicals of the 2- tetrahydrofuryl and especially 2-tetrahydropyranyl radicals; and finally also a silyl group trisubstituted by identical or different hydrocarbon radicals, in particular a tri-lower alkylsilyl group such as the trimethylsilyl and dimethyl-tert-butylsilyl groups. As a special one The case of etherified hydroxyl groups is 17a, 20; 20,21-bismethylenedioxy grouping should also be mentioned.

An esterified hydroxyl group is particularly one which is esterified by a carboxylic acid, it can but, as said above, also be a lactonized hydroxyl group,

The main carboxylic acid components of an esterified hydroxyl group are those in the steroid industry customary carboxylic acids into consideration, for example monocarboxylic acids with a maximum of 18 carbon atoms, such as aliphatic carboxylic acids, especially formic acid or a lower alkanecarboxylic acid, their lower alkyl radical one of the above is, primarily the

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a!

Propionic, butyric, isobuttered, valeric, isovaleric, oenanthic and diethyl acetic acid and above all the caproic, Trimethyl acetic and acetic acid; but also corresponding halogenated lower alkanecarboxylic acids, such as chloroacetic acid, Trichloro ^ or trifluoroacetic acid; as well as cycloaliphatic, cycloaliphatic-aliphatic and aromatic carboxylic acids, e.g. optionally by halogen, such as fluorine, chlorine or bromine, hydroxy, lower alkoxy, lower alkyl and / or nitro-substituted benzoic acids or corresponding aryl or aryloxy-lower alkanecarboxylic acids, but also corresponding dicarboxylic acids with a maximum of 12 carbon atoms, e.g. the amber, glutar, Adipic and phthalic acid.

The 6ß, 7- which can be produced according to the invention -Methylene-3-oxo-4-ene steroids are useful as intermediates for the synthesis of valuable pharmaceutical Active ingredients, especially for hormone therapy, and as an additive in animal feed. Some of these, e.g. as will be particularly emphasized below, at the same time have a biological effectiveness themselves and can therefore be used directly as active ingredients in the above-mentioned areas of application be used.

Steroid compounds with the 6ß, 7-methylene -3-oxo-4-ene groupings were previously created by the addition of the methylene group to the 6,7 double bond a corresponding 3-oxo-4,6-diene prepared; as

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The reagent used was dimethyloxosulfonium methylide. The addition is by no means stereospecific and always results in mixtures of 6a, 7- and 6 / 3,7-epimers, in which mostly the a-epimer more or less predominates, see e.g. NH Dyson, JA Edwards and JH Fried: Tetrahedron Letters, 1966, 1841-1844. This lack of stereospecificity was also observed with the introduction of the analogous dichloro or difluoromethylene group through the addition of dichloro or difluorocarbene to the 6,7 double bond, see e.g. C. Beard, B. Berkoz et al., Tetrahedron 1969 , 25, 1219. Because the resulting epimers differ very little in their physical properties, they can be separated from one another with great difficulty, with high losses, and often only incompletely. The separation methods used, for example thin-layer chromatography, repeated fractional crystallization, etc., are completely unsuitable for industrial production because of their complexity. Therefore, the solution to the problem was to be sought in the most stereospecific synthesis of this grouping.

As has now been found, surprisingly, the addition of the methylene group to the 6,7- -Double bond extremely stereospecific, practically under exclusive formation of the 6ß, 7-methylene epimer, if you have a steroid compound that contains the 6-ene-36,5ß-

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-diol Gruppierung.enthält, or a 3-ether or 3-ester thereof, with ei ^ i cw zinc / copper methylene iodide reagent

implements. In the 6ß, 7-methylene-3fe, 5ß- -dihydroxy grouping can, if appropriate after

previous release from the - - ~~

etherified or esterified form, the 3-hydroxyl group dehydrate with conventional oxidizing agents and the resulting 6ß, 7-methylene-5ß-hydroxy-3-oxo group dehydrate surprisingly smoothly under mild conditions to the desired 6β, 7-methylene-3-oxo-4-ene grouping.

These 3 or 4 reaction stages (methylene addition, Release of the hydroxyl group, dehydration and dehydration, which may have to be carried out) do not have to be can be carried out one after the other in an uninterrupted sequence, but one can choose between the individual according to the invention Steps of appropriate operations, e.g. for converting the 17-position substituents, optional turn on.

The method according to the invention is preferably used carried out so that a compound of formula III

(HD

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where η and R are the above-mentioned general and particular

2 have highlighted meanings and R for an α- or in particular / 3-oriented hydroxyl group which is etherified by an easily cleavable protective group or by a Carboxylic acid can be esterified, stands, one after the other

a) reacts with a zinc / copper methylene iodide reagent,

b) an existing 3-ether resp.

3-ester converts to a corresponding 3-hydroxy compound,

c) the corresponding 6ß , 7-methylene-3fe, 5ß-diol treated with an oxidizing agent for the purpose of dehydrogenating the 3-hydroxyl group

d) the resulting sweet , 7-methylene-5ß-hydroxy-3-oxo compound is dehydrated. If desired, further optional reactions for converting the group R within the meaning given above can be inserted between the reaction stages a) - d) mentioned.

The organometallic reagent for reaction step a) according to the invention, i.e. the zinc / copper methylene iodide reagent, is made in situ by placing methylene iodide on finely divided zinc / copper alloy (Diiodomethane, CH ^ I «) can act. The one mentioned Zinc / copper alloy is made by treating finely divided zinc, preferably in the form of zinc dust, with a copper salt, in particular a copper (II) salt, such as copper sulfate. Usually one leads

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the preparation of the zinc / copper alloy in an aqueous medium; at the end the water is decanted off and replaced by a suitable organic solvent by repeated decantation. The specification of E. Le Goff: J. Org. Chem. 1964 , .22, 2048 can serve as an example of an advantageous variant of the preparation of the alloy. The reaction of the zinc / copper alloy with methylene iodide takes place with the exclusion of water and alcohols in a saturated open-chain or cyclic ether or polyether, or a mixture of two or more of these solvents, at temperatures ranging from about 10 ^° C. to the boiling point of the reaction mixture extend. If desired, the reaction can be started by activating it with a small amount of iodine. The ethers and polyethers already mentioned come in particular

symmetrical di-lower alkyl ethers, such as diethyl or Diisopropyl ether, and polyethers derived from glycols, such as ethylene glycol dimethyl or diethyl ether and diethylene glycol dimethyl ether; also tetrahydrofuran, tetrahydropyran and dioxane can also be considered. Tetrahydrofuran and especially diethyl ether and primarily ethylene glycol dimethyl ether are particularly advantageous (1,2-dimethoxyethane). Other aprotic solvents or diluents can also be added to these ethers

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such as, for example, aliphatic or aromatic inert hydrocarbons such as hexane, cyclohexane, benzene or toluene.

The reaction of the steroid with the reagent usually takes place directly after the preparation of the reagent by adding the steroid compound to be converted, preferably dissolved in one of the solvents mentioned. The reaction is usually carried out at elevated temperature, preferably under atmospheric pressure at the boiling point of the reaction mixture. You can also work at constant volume by distilling off the solvent while adding the steroid, or reacting with the nasal organometallic reagent by adding the excess zinc / copper alloy and a small amount of the finished organometallic reagent in the medium mentioned at the same time Add steroid and methyl en iodide in portions. The reaction is usually carried out at atmospheric pressure, but it is also possible to work under increased pressure. - After the reaction has ended, the reaction mixture is hydrolytically decomposed; the conditions for the hydrolytic work-up are those which are usually used for this purpose in the chemistry of organometallic compounds, in particular organozinc compounds. As an example of the implementation described above,

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including the preparation of the organometallic reagent and the work-up, the procedure according to HE Simmons et al., J. Am. Chem. Soc. 1958 , 80 , 5323 and 1964 , J36, 1347.

The release of the 3-hydroxyl group mentioned under process step b) according to the invention is analogous only when the starting materials of formula III are veneered,

wherein R is a hydroxyl group which is obtained by esterification or etherification, as indicated above for formula III,

2 is protected, performed; if R is a free hydroxyl group, this reaction stage falls naturally path. The release according to stage b) takes place in a manner known per se, preferably by hydrolysis. By the easily cleavable protective groups are hydrolyzed with etherified hydroxyl groups (including the silyloxy groups) is preferably carried out under acid catalysis, the mildest possible conditions being recommended in each case. the Hydrolysis takes place in the presence of an inorganic acid, e.g. sulfuric acid or a hydrohalic acid, such as hydrochloric, bromic or hydroiodic acid, or an organic sulphonic acid such as p-toluenesulphonic acid or sulphosalicylic acid, or preferably a moderately strong carboxylic acid such as oxalic acid, acetic acid or formic acid. From benzyloxy and triphenylmethoxy groups, the hydroxyl group can also be hydrogenolytically, e.g. by Hydrogenation over palladium catalyst, release. the

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Hydroxyl groups esterified by carboxylic acids can also be hydrolyzed under acidic conditions; however, they are preferably hydrolyzed with base catalysis. The basic catalysts used are preferably hydroxides, carbonates or hydrogen carbonates of the alkali metals, in particular of sodium or potassium. Esterified hydroxyl groups can also be released reductively, for example by the action of an ester reducing agent such as a complex hydride or diborane. I _n compounds which, in addition to the etherified or esterified 3-hydroxyl group mentioned, also contain hydroxyl groups of the same type in 17- and / o '.! , i. "21-position, the latter are usually released at the same time as the former.

The dehydrogenation of the 3-hydroxyl group to the 3-oxo group according to reaction step c) is also carried out made in a known manner. Compounds of the hexavalent are considered to be preferred oxidizing agents Chromium, such as chromium trioxide, chromic acid and its alkali metal salts, which is an advantageous reaction medium Lower alkanecarboxylic acids, such as acetic or propionic acid, or pyridine or, in particular, acetone, if appropriate in combination with a halogenated lower alkane, such as dichloromethane or chloroform, and / or in the presence aqueous sulfuric acid is used. Another alternative

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the oxidation of the hydroxyl group is the Oppenauer oxidation, i.e. the oxidation with a ketone, such as acetone or cyclohexanone, under the catalytic influence of an aluminum lower alkoxide, such as aluminum isopropoxide; under certain circumstances takes place under the conditions of oxidation or work-up of the reaction mixture at least partially a spontaneous dehydration according to reaction stage d).

The dehydration indicated under reaction stage d) according to the invention also takes place in an known way by splitting off the elements of water. The dehydration can be by bases, but in particular are catalyzed by acids; a particularly advantageous implementation consists in heating the corresponding 6 / 3,7-methylene-5/3-hydroxy-3-oxo compound in acetic acid. In the latter case, this treatment is preferably carried out after the previous dehydration without purification of the Intermediate carried out.

The reactions which can be carried out optionally and which can, if desired, be between the inventive Reaction stages a) - d) include, in particular, the following common conversions in steroid chemistry: acid-catalyzed hydrolysis of a ketalized 17-oxo groupj Conversion of the 17-oxo group into the 17/3 hydroxy group, if necessary with simultaneous introduction of an optionally substituted lower aliphatic hydrocarbon radical; Hydrogenation of an acetylenic hydrocarbon

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rests; Esterification or etherification of a hydroxyl group; and closing a lactone ring in a hydroxycarboxylic acid. The first three conversions are advantageously connected to step a) according to the invention, the penultimate conversion takes place preferably, in particular in the case of tertiary hydroxyl groups, after process stage c). The lactonization can, under certain circumstances, be carried out simultaneously with process step d), in particular when heating in Acetic acid, done spontaneously.

The optional acid-catalyzed hydrolysis of the 17-oxo group is advantageously carried out in a manner known per se under conditions analogous to those given above for the hydrolysis of easily split off ethereal protective groups.

The optional conversion of the 17-oxo group to the

17β-hydroxyl group occurs primarily through reduction. the Reduction is carried out in a manner known per se; it is advantageous to use diborane or complex hydrides for this purpose, in particular those of aluminum or boron with an alkali or alkaline earth metal, such as sodium aluminum hydride, calcium borohydride, Lithium borohydride, but especially lithium aluminum hydride and especially sodium borohydride, or its derivatives, in which one or more hydrogen atoms pass through Lower alkoxy radicals are replaced, such as methoxysodium borohydride and, in particular, tri-tert-butoxylithiumaluminum hydride. The choice of the solvent and the reduction conditions depends on the reducing agent used and

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corresponds to the generally known principles. As already said, you can convert the 17-oxo group into the 17-hydroxyl group also under simultaneous Introduction of an optionally substituted lower aliphatic hydrocarbon radical, e.g. perform one of the above-mentioned by entering in in a manner known per se, a corresponding oxo compound is reacted with a corresponding organometallic compound. if the hydrocarbon radical to be introduced is a lower alkyl radical is, the organometallic compound is a Grignard compound, e.g. a lower alkyl magnesium halide such as methyl magnesium bromide or iodide, or lower alkyl lithium, like methyllithium preferred; when a 1-alkynyl radical, e.g. 3- (2-tetrahydropyranyloxy) propynyl, 3, 3-ethylenedioxyprc) pynyl, 3-hydroxypropynyl and especially the ethynyl radical, is to be introduced, it is advantageous to use a corresponding alkali metal compound, e.g. sodium or potassium acetylide or, in particular, lithium acetylide. In the latter case, lithium acetylide is particularly advantageous to use in the form of its complex with ethylenediamine. The introduced ethynyl residue can then be further converted, by contrasting the terminal hydrogen atom in it, for example exchanges a carboxyl group. It does this by treating with a Grignard compound and the subsequent one Implementation of the resulting u / magnesium halide with carbon dioxide. (Immediately after the introduction of a acetylenic radical or the carboxylation can be

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cancel the acetylenic 20 (21) bond, as further is described in detail below.) "1 ° more analog Way is also the introduction of a disub-

substituted amino group-substituted lower alkyl radicals, e.g. a 7-di-lower alkylaminopropyl radical, in particular one of those mentioned above as preferred carried out; as a suitable organometallic reagent is above all the corresponding 7-Diniederalkylaminopropyllithium to mention.

The optional saturation of the acetylenic bonds can, for example, in a manner known per se catalytic hydrogenation take place. It can be threefold Bond in the first stage provide a double bond, which may lead to a - ———

simple bond is further saturated. With the catalytic Hydrogenation works with normal or normal water gas increased pressure under conditions of heterogeneous or homogeneous catalysis. The catalysts for the former are finely divided Metals, e.g. Raney metals such as Raney nickel, or precious metals, such as palladium, platinum or rhodium, which may be distributed on a carrier such as calcium carbonate or barium sulphate are particularly well suited. In particular, complex rhodium compounds are used for homogeneous catalysis, e.g.

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Tris - (triphenylphosphine) rhodium (I) chloride. For selective Hydri.erui-ig a triple bond to a double bond it is advantageous to use the Lindlar catalyst, i.e. a palladium catalyst partially deactivated by lead.

The hydrogenation conditions are to be chosen so that the cyclopropane ring of the 6ß, 7-methylene group is not attacked will.

The optional esterification or etherification of hydroxyl groups in obtained compounds occurs likewise in a manner known per se. For esterification, for example, the compound to be esterified is treated with excess acid itself, such as with formic acid, or with a reactive derivative thereof, for example with a derivative of a the acids specified above, in particular with an anhydride or acid halide, advantageously in the presence of a tertiary base, v; ie pyridine, quinoline or N-ethyl-piperidine. Heavy esterifiable hydroxyl groups, such as a tertiary 17a-hydroxyl group, can advantageously be selected from the catalytic The action of organic sulphonic acids, e.g. benzene, p-toluene, salicylic or camphor sulphonic acid, by means of a Esterify acid anhydrides. For etherification, for example, the compounds to be etherified are treated with reactive ones Derivatives of alcohols, e.g. with esters with strong acids, such as halides, sulphates or sulphonic acid esters, whereby

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the alcohol component corresponds to the meanings given above for an etherified hydroxyl group. Preferably leads the reaction is carried out in the presence of basic agents. For the formation of tetrahydropyranyl ethers and analog 1- -Lower alkoxy lower alkyl ethers are used as a reagent preferably a corresponding unsaturated derivative such as 2,3-dihydropyran or a vinyl lower alkyl ether, e.g. vinyl butyl ether, and carries out the reaction under conditions acid catalysis, preferably in the presence of an organic sulphonic acid. - The silyl ethers, e.g. the hydroxy compounds etherified with tri-lower alkyl groups, such as trimethylsilyl or dimethyl-tert-butyl-silyl groups can by treating with an appropriate silylating agent, such as trimethylchlorosilane, dimethyl-tert- -butylchlorosilane, hexamethyldisilazane, trimethylsilylamine, trimethylsilyldiethylamine, dimethyl-tert-butylsilylimidazole, N-trimethylsilylacetamide or N, N-bis (trimethylsilyl) - acetamide, in an anhydrous solvent such as dimethylformamide, dimethyl sulfoxide or acetonitrile, if appropriate in the presence of an anhydrous base such as triethylamine, piperidine, pyridine or imidazole.

The optional closure of a lactone ring,

insofar as they do not spontaneously, as mentioned above, in the case of the invention Process stage d) takes place, usually happens

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spontaneously when a carboxyl group present as a salt is released by acidic acids. One can do the lactonization also by acid catalysis and / or the use of dehydrating agents, such as acetic anhydride, anhydrous Accelerate copper sulfate, molecular sieves, or by azeotropic distillation.

Preferred starting materials for the inventive

Processes are those compounds of formula III wherein

η stands for the number 1, R a free ß-hydroxyl group and R has one of the following meanings: a free or ketalized oxo group; a ß-acetyl group (= a-oxoethyl group) together with a hydrogen atom; or an etherified or esterified ß-hydroxyl group together with hydrogen or a lower alkyl. . R preferably denotes a substituent specified at the outset under the formula II, especially one in which R stands for an oxo group, or a corresponding open-chain form thereof, i.e. a free 17β-hydroxyl group along with one by hydroxymethyl, formyl or in particular Carboxyl substituted ethyl radical in ß-position. As has already been said above, the latter carboxyl group also be in the form of a salt.

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Preferred ways of carrying out the process according to the invention are those which lead to end products of the formula I in which R has the preferred meanings mentioned, and including in particular those in which the synthesis stages a) - d) follow one another directly. The use of the preferred starting materials with a free 3-hydroxyl group is also associated with the advantage that process step b) is omitted.

A particularly preferred implementation of the invention Process relates to the preparation of 20-spirox -4-ene compounds of the formula

.la

IA,

la
wherein R denotes two hydrogen atoms or an oxo group, which is characterized in that starting from a compound of the formula

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IIIA,

la
where R has the meaning given, carries out the above process steps a), c) and d).

As is known from the literature, see German Offenlegungsschrift No. 1,914,507 and British Patents No. 1,361,362 and No. 1,403,800, are the compounds of Formula IA both in the cyclic form shown and in the open-chain form of the corresponding hydroxy acid or their alkali metal salts, highly effective aldosterone inhibitors. They antagonize those caused by aldosterone and analog-acting steroids cause salt retention and are therefore used in the alleviation of diseases, in which the secretion of aldosterone is increased, as in heart failure with congestion symptoms, Nephrosis and kidney cirrhosis.

The 6-en-3 />, 5β-diol steroids used as starting materials for the process according to the invention, in particular those of the formula III characterized above,

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are new and are also made using a novel manufacturing process obtained by a corresponding 3 £ -hydroxy -5jB, 6-epoxide, in particular one of the formula

(CH ₂ )

2
in which n, R and R have the meanings given above, treated successively with a selenol, a peroxidic oxidizing agent and a base.

The selenol used is in particular a

Lower alkane or arenselenol, preferably one optionally by lower alkyl, lower alkoxy, nitro groups and / or Halogen atoms substituted benzene selenol (selenophenol), especially benzene selenol. Because of his sensitivity

against oxidation, the selenol used is preferably prepared in situ directly before the reaction by with the exclusion of atmospheric oxygen, a corresponding symmetrical diselenide in a manner known per se, e.g. with zinc and an acid such as hydrochloric acid or acetic acid,

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or reduced with a complex hydride, preferably sodium borohydride. The addition of the selenol the steroid with the formation of the corresponding 5ß-hydroxy- -6a-sel.enids is also excluded Atmospheric oxygen in an organic solvent such as a lower alkanol or ether, e.g. one of the above mentioned, or a mixture of several such solvents, carried out, usually at a higher Temperature, advantageously in the vicinity of the boiling point of the reaction mixture, works.

The peroxidic oxidizing agent is in particular an inorganic peroxy acid, such as mono- or diperoxysulfuric acid, or an alkali metal salt thereof, or in particular an organic peroxy acid, such as peracetic, perbenzoic, m-chloroperbenzoic and monoperoxyphthalic acid, in free form or in the form of corresponding alkali metal salts. However, hydrogen peroxide, preferably in the usual commercial form as an approximately 30 % aqueous solution, can also be used with advantage as the peroxidic oxidizing agent. The oxidation in which the 6a-selenide group (-Se-)

is converted into the 6a-selenonyl group (-SeO ₂ -) is carried out in a manner known per se, preferably in a weakly acidic manner

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or a neutral medium using organic solvents, preferably those that are miscible with water, e.g. the alcohols, ethers and polyethers mentioned above. The reaction temperature usually ranges between about -25 to + 35 °.

To split off the 6a-selenonyl group in the 6a-

-Selenonyl-3 &, 5ß-diol, in particular a 6a-phenylselenonyl -3 ^, 5/3-diol, with formation of the desired 6,7 double bond of the steroid of the formula III are, in particular, organic bases such as tertiary amines, for example tri-lower alkylamines or aryl, especially phenyl-di-lower alkylamines, or heterocyclic bases, especially those which are at least partially saturated, for example N-ethylpiperidine, N-methylpyrrolidine or N, N ¹ -dimethylpiperazine, are suitable. A particularly advantageous base is 1,5-diazabicyclo [4,3, onon-5-ene. The reaction can be carried out in excess base as solvent, or an inert organic solvent, preferably one which is miscible with water, such as, for example, pyridine and its homologues, can be used. The work is usually carried out at an elevated temperature, in particular between about 45 to about 150 ^° C., optionally also under increased pressure. It is advantageous to allow the reaction to proceed in the absence of atmospheric carbon dioxide and oxygen and under anhydrous conditions.

The starting materials required for the reaction already described, i.e. 5β, 6-epoxy-3i-hydroxy-steroids, e.g. of the formula IV are known or known per se

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Methods, e.g. through the addition of the elements of the sub-bromine Acid to the 5,6 double bond and the subsequent dehydrobromination using a base, accessible.

The compounds, substituents and meanings of the symbols in the Connection with the formulas I to III were mentioned as preferred.

The invention also relates to those embodiments of the above method, in which one on runs out of compound obtainable as an intermediate product at some stage and carries out the missing steps, or in which a starting material is formed under the reaction conditions.

The invention is explained in more detail in the following examples without thereby limiting its scope. The temperatures are given in degrees Celsius. The nomenclature used is the root structure 20-spiroxane of the formula

21

while the other principles of conventional steroid nomenclature are retained.

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To a mixture of 14.4 g of diphenyls! is el en id in 240 ml absolute alcohol, while stirring and cooling with ice-water, 3.68 g of sodium borohydride is added in portions within 30 minutes added in a stream of nitrogen. After a further 30 minutes, the mixture is treated with 6 ml of glacial acetic acid and then with 4.76 g of 5 [beta], 6-epoxy-3/3-hydroxy-20-spiroxan-21-one acetate offset. After boiling for 24 hours, the cooled reaction solution is poured into water and extracted several times with methylene chloride. The organic phase is washed with dilute sodium chloride solution, dried and in vacuo evaporated, the residue dissolved in toluene and chromatographed on 200 g of silica gel. First, with toluene the Diphenyl diselenide eluted. Subsequently, by eluting with a mixture of toluene-ethyl acetate (7: 3) the 3ß, 5ß- -Dihydroxy-öa-phenylseleno- ^ O-spiroxan ^ l-one-S-acetate obtained. After crystallization from ether, the substance melts

Ϋ
243-247 °.

The 5/3, 6-epoxy-3ß-

Hydroxy-20-spiroxan-21-one acetate is obtained as follows; a) A stirred solution of 10g 3ß-hydroxy-20-spirox-5-en-21-one acetate in 100 ml of dioxane is successively with 7.3 ml diluted perchloric acid (prepared by diluting 4.66 ml of 70 percent perchloric acid with 20 ml of water), 5 ml Water and, while cooling with ice, 5 g of N-bromoacetamide are added within 15 minutes. After stirring for 30 minutes at The reaction mixture is again at room temperature

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Ice-water cooled with 60 ml of a 1 percent sodium thiosulfate solution and then mixed with water and extracted with ether. The organic extracts come with Washed water, dried and evaporated in vacuo at room temperature. By crystallizing the residue 5α-bromo-3β, 6β-dihydroxy-20-spiroxane-21-one--3-acetate of melting point 160 ° -162 ° (decomposition) is obtained from ether. Umb'sen from acetone-methanol increases the melting point to 164-165 ° (decomposition).

By stirring the residue, which remains after evaporation of the mother liquors, with zinc / copper alloy and The starting material (5-en-3-ol acetate) is obtained back in glacial acetic acid.

b) A solution of 1.8 g of the bromohydrin acetate obtained under a) in 25 ml of anhydrous dioxane in a stream of nitrogen with 900 mg of 1,5-diaza-bicyclo [4,3,0] non-5-en under After rinsing, 5 ml of dioxane are added. After 30 minutes the reaction mixture is treated with 2.25 ml of glacial acetic acid Poured saturated sodium hydrogen carbonate solution and extracted with toluene. The organic extracts come with Washed water, dried and evaporated in vacuo. Obtained by chromatography of the residue on silica gel one 5β, 6-epoxy-3β-hydroxy-20-spiroxan-21-one acetate, m.p. 187-190 '

709842/0832

27U891

To a mixture of 1.16 g of sodium acetate and 5 g 3β, 5β-dihydroxy-6a-phenylseleno-20-spiroxan-21-one-3-acetate 1.16 ml of glacial acetic acid, 94 ml of ethanol and 47 ml of tetrahydrofuran are added dropwise with stirring and ice-cooling within 20 minutes Add 18.8 ml of 30 percent hydrogen peroxide and stir for a further 2 1/4 hours at room temperature. The mixture will emptied onto dilute sodium chloride solution, taken up in methylene chloride, washed with dilute sodium chloride solution, dried and evaporated in vacuo. The residue is dissolved in 190 ml of pyridine and in a closed flask in Nitrogen atmosphere with 24 ml 1,5-diaza-bicyclo [4,3,0] non-5-en heated to 63 ° for 20 hours. The reaction mixture is then treated with 24 ml of glacial acetic acid while cooling with ice-methanol added, diluted with 1.5 l of water and taken up in toluene. The organic phase is successively mixed with dilute sodium hydrogen carbonate solution and washed with water, dried and evaporated in vacuo. The residue is dissolved in toluene Solution filtered through 24 g of Flor. '. Sil and the adsorbent was washed with 1 liter of a mixture of toluene-ethyl acetate (4: 1). The eluates are evaporated and the residue is crystallized from methylene chloride-ether. It is 3ß, 5/3-dihydroxy -20-spirox-6-en-21-one-3-acetate obtained, which melts at 185-194 ° after further crystallization.

7 09842/0832

27U891

A solution of 2 g of the 3-acetate obtained above in 200 ml of methanol is mixed with 40 ml of 1N sodium hydroxide solution under nitrogen and left to stand for 6 hours. The mixture is acidified with 78 ml of 1N hydrochloric acid, emptied after 6 minutes to 1.2 l of diluted sodium chloride solution and taken up by repeated extraction in methylene chloride. The organic solutions are washed with dilute sodium chloride solution, dried and evaporated in vacuo; the residue gives the 3β, 5/3-dihydroxy-20-spirox-6-en-21-one, mp ₄ 203-204 ° by crystallization from methylene chloride.

Example 3 .

A mixture of 30 ml of ether, 4.32 g of methylene iodide and 1.62 g of zinc / copper alloy is added while stirring with 168 mg Iodine added. As soon as discoloration occurs within about a minute, the mixture is mixed with a solution of 150 mg 3 / 3,5β-Dihydroxy-20-spirox-6-en-21-one in 6.8 ml of 1,2-dimethoxyethane 3.6 ml of ether were added while rinsing, and the mixture was refluxed for 17 1/2 hours in a stream of nitrogen. Fixed proportions are suction filtered and washed successively with methylene chloride, water, methanol and methylene chloride. The filtrate is diluted with saturated ammonium chloride solution and extracted with methylene chloride. The organic Phase is washed with dilute sodium chloride solution,

• 7 09842/0832

27Η89Ί

dried and evaporated in vacuo. The residue, by preparative thin layer chromatography (silica gel; toluene -Acetone / 7: 3), it gives 3ß, 5ß-dihydroxy-6ß, 7- -methylene-20-spiroxan-21-one in the form of a light yellow oil.

Example 4 .

A mixture of 43 mg 3ß, 5ß-dihydroxy-6ß, 7-methylene -20-spiroxan-21-one and 50 mg of chromium trioxide in 3 ml of pyridine is stirred for 16 hours at room temperature, with a A solution of 200 mg of sodium sulfite in 4 ml of water is added and the mixture is diluted with a further amount of water. The mixture will extracted with toluene and added 1.5 ml of glacial acetic acid to the toluene extract. The aqueous phase is mixed with 2 ml of glacial acetic acid added and extracted twice with toluene. The organic extracts are combined, washed twice with water, dried and evaporated in vacuo. The residue is heated with 3 ml of glacial acetic acid in a nitrogen atmosphere for a Hour to 80 ° and the volatile components evaporated in vacuo. The residue is subjected to preparative thin layer chromatography (Silica gel; toluene-acetone / 4: 1). The 6ß, 7-methylene-20-spirox-4- -en-3,21-dione is recrystallized from ether, m.p. 178.5-179 *.

909842/0832

Claims (1)

Claims 27U891 1. Process for the preparation of 6ß, 7-methylene-3- -οχο-4-ene steroids of the general formula (CH ₂ ) _n (D, in which η denotes the number 1 or 2 and R denotes an optionally ketalized oxo group, an optionally etherified one or esterified hydroxyl group together with a hydrogen atom or an optionally substituted lower aliphatic hydrocarbon radical, or represents a hydrogen atom together with an optionally substituted lower alkyl radical, characterized in that that a compound of the formula III (III) 709842/0832 ORIGINAL INSPECTED ^X 27U891 2 wherein η and R have the meanings given above and R stands for a cc- or β-oriented hydroxyl group, which by an easily removable protective group can be etherified or esterified by a carboxylic acid, stands in sequence a) reacts with a zinc / copper methyl iodide reagent, b) etherified or esterified in an existing 3-position 6ß, 7-methylene-3 |, 5-diol releases the 2-hydroxyl group, c) the 6β, 7-methylene-3 |, 5β-diol obtained with an oxidizing agent treated to dehydrate the 3-hydroxyl group d) the 6β, 7-methylene-5β-hydroxy-3-oxo compound obtained dehydrated, with one or more further optional ones if desired between process steps a-d Reaction to convert the group R can insert within the meaning given above. 2. The method according to claim 1, characterized in that the symbol η in compounds of formulas I and III for the number 1 stands. 3. The method according to claim 1, characterized in that 2
that the symbol R in compounds of the formula III ß-oriented 4. The method according to claim 1, characterized in that 2 that one compounds of the formula III in which R is a ß-oriented means free hydroxyl group, according to process steps a), c) 709842/0832 27U891 and d) implementing step b) omitting. 5. The method enjoyed any of claims 1-4, characterized characterized in that the symbol R in compounds of the formula I and III is a radical of the sub-formula CH ₂ -CH ₂ \ - R ¹ (ID means where R has two hydrogen atoms, an oxo group, or represents a lower alkoxy group together with a hydrogen atom. 6. The method according to any one of claims 1-4, characterized characterized in that the symbol R in compounds of the formulas I and III for a ß-oriented free hydroxyl group together with an ethyl radical, which is in its ß-position by an optionally etherified or esterified hydroxymethyl group, an optionally acetalized formyl group or an optionally esterified carboxyl group is substituted is, stands. 7. The method according to claim 1, characterized in that that, if desired, one can choose between the Process stages a) -d) a acid-catalyzed hydrolysis of a ketalized 17-oxo group is added. 8. The method according to claim 7, characterized in that 709842/0832 27U891 the hydrolysis is carried out after process stage a). 9. The method according to claim 1, characterized in that that, if desired, between the process steps according to the invention a) -d) a conversion of the 17-oxo group into the 17β-hydroxy group, optionally with simultaneous introduction of an optionally substituted lower aliphatic hydrocarbon radical, applies. 10. The method according to claim 9, characterized in that that the conversion of the 17-oxo group after process step a) or after the release of the oxo group in accordance with Claim 8 carries out. 11. The method according to claim 9 or 10, characterized in that that the 17-oxo group is reduced to the 17β-hydroxyl group by means of a complex hydride. 12. The method according to claim 9 or 10, characterized in that that by reacting with a corresponding organometallic compound, the 17-oxo group is converted into the 17β-hydroxyl group converts and at the same time an optionally substituted lower aliphatic hydrocarbon radical introduces. 13. The method according to claim 1, characterized in that that, if desired, between the process according to the invention stages a) -d) a hydrogenation of an acetylenic carbon 70 9842/0832 inserts hydrogen residues. 14. The method according to claim 1, characterized in that, if desired, between the inventive Process stages a) -d) an esterification or etherification a hydroxyl group. 15. The method according to claim 1, characterized in that that, if desired, between process steps a) -d) according to the invention, a lactone ring is closed in a hydroxycarboxylic acid. 16. The method according to claim 1, characterized in that 20-spirox-4-ene compounds of the formula IA, where R is two hydrogen atoms or an oxo group, manufactured by making a compound of the formula 909842/0832 27U891 .la (IIIA), la
where R has the meaning mentioned, successively with a zinc / copper methylene iodide reagent for the purpose of 6ß, 7-methylation, with an oxidizing agent for the purpose of dehydrating the 3-hydroxyl group to the oxo group and with a dehydrating agent for the purpose of splitting off the 5ß-hydroxyl group to form the 4, 5 double bond converts. 17. The method according to claim 16, characterized in that a compound of the formula IIIA is reacted in which the 3-hydroxyl group is ß-oriented. 18. The method according to claim 1 or 16, characterized in that that a compound of hexavalent chromium is used as the oxidizing agent. 19. The method according to claim 18, characterized in that chromium trioxide is used in pyridine. 20. The method according to claim 16, characterized in that the oxidation product is dehydrated in acetic acid heated. 21. Process for the preparation of compounds of the formula III 709842/0832 27U891 (CH ₀ ) 2'n (III) where η denotes the number 1 or 2 and R denotes an optionally ketalized oxo group, an optionally etherified or esterified hydroxyl group together with a hydrogen atom or an optionally substituted lower aliphatic Hydrocarbon radical, or a hydrogen atom together with represents an optionally substituted lower alkyl radical 2
and R represents an α- or β-oriented hydroxyl group which can be etherified by an easily cleavable protective group or esterified by a carboxylic acid, characterized in that a corresponding 3§-hydroxy-5β, 6-epoxide of the formula (CH ₀ ) 2'η (IV), wherein n, R and R have the meaning given above, in succession with a selenol, a peroxidic oxidizing agent and a base treated. 709842/0832 -jii- 27H891 22. The method according to claim 21, characterized in that that the symbol η in compounds of the formulas III and IV stands for the number 1. 23. The method according to claim 21, characterized in that 2
that the symbol R in compounds of formulas III and IV is ß-oriented. 24. The method according to claim 21, characterized in that the symbol R in compounds of formulas III and IV a group of the sub-formula
CH ₂ -CH ₂ :) ^c - ^r1 α « he means, in which R, two hydrogen atoms, an oxo group, or represents a lower alkoxy group together with a hydrogen atom. 25. The method according to claim 21, characterized in that the symbol R in compounds of formulas III and IV is a p-oriented free hydroxyl group together with a through
Hydroxymethyl, formyl or carboxyl is an ethyl radical substituted in the β-position. 26. The method according to claim 21, characterized in that it is marked chr.et, that one compound of the formula 709842/0832 (IIIA), la
wherein R is two hydrogen atoms or an oxo group. 27. The method according to claim 21 or 26, characterized in that that compounds of the formula III or IIIA are prepared in which a ß-oriented hydroxyl group in the 3-position stands. 28. The method according to any one of claims 21-27, characterized characterized in that it is reacted with phenylselenol. 29. The method according to any one of claims 21-27, characterized characterized that one with about 30-% aqueous hydrogen peroxide oxidized. 30. The method according to any one of claims 21-27, characterized characterized in that one with 1,5-diazabicyclo [A, 3.0] non-5-en treated as a base. 31. The method according to any one of claims 21-30, characterized characterized in that a 3-hydroxyl group present in the starting material in esterified form is subsequently replaced by basic 709842/0832 27U891 Hydrolysis releases. 32. The method according to one of claims 1 to 31, characterized characterized in that one starts from a compound obtainable as an intermediate product at any stage and carries out the missing steps, or forms a starting material under the reaction conditions and / or a compound in the form of a salt thereof is used or isolated. Compounds of formula III (CH ₂ ) (III) where η denotes the number 1 or 2, R optionally denotes ketalized oxo group, an optionally etherified or esterified hydroxyl group together with a hydrogen atom or an optionally substituted lower aliphatic hydrocarbon radical, or a hydrogen atom together with an optionally substituted lower alkyl radical, and R is an α- or ß-oriented hydroxyl group, which can be etherified by an easily removable protective group or esterified by a carboxylic acid, represents. Compounds according to claim 33, wherein R is a radical 709842/0832 the partial formula CH ₀ -CH \ - Rl 27U891 (H) denotes in which R represents two hydrogen atoms, an oxo group, or a lower alkoxy group together with a hydrogen atom, or a corresponding open-chain form thereof, ie a free 17β-hydroxyl group together with an ethyl radical substituted in β-position by hydroxymethyl, formyl or carboxyl . 35. Compounds according to claim 33, characterized by the formula .la (ITIA), la wherein R is two hydrogen atoms or an oxo group :. 36. Compounds according to one of claims 33-35, characterized characterized in that the substituent is ß-oriented in the 3-position. 709842/0832 - / 3 37. Compounds of the general formula (CH ₂ ) _n 27U891 (D. where η denotes the number 1 or 2 and R denotes an optionally ketalized oxo group, an optionally etherified one or esterified hydroxyl group together with a hydrogen atom or an optionally substituted lower one aliphatic hydrocarbon radical, or a hydrogen atom together with an optionally substituted lower alkyl radical when they are claimed in claim 1 Process, or an obvious chemical equivalent thereof. The new compounds described in the examples. 709842/0832